The heritability of alcoholism is 40-60% in both men and women, but, as in other complex psychiatric diseases, it has proved difficult to identify causative genes. Intermediate phenotypes are associated biological traits that may be influenced by variation at fewer genes and may mediate different aspects of the disease. The intermediate phenotypes we are studying include resting EEG phenotypes, event-related potentials (ERPs) and heart rate variability (HRV). We have identified an intermediate phenotype for alcoholism vulnerability, the low voltage alpha (LVA) EEG, a normal, traitlike heritable variant of the resting EEG, present in 7-14% of the population, in which the alpha rhythm is virtually absent. We have a complete data set, including EEG and ERP phenotypes, blind-rated DSM-III-R psychiatric diagnoses, psychometric tests and DNA on 247 predominantly Caucasian individuals from Bethesda, MD. We have shown that LVA is associated with alcoholism, particularly when accompanied by anxiety disorders. Moreover, we found that LVA individuals, irrespective of clinical state, had reduced auditory and visual P300 ERP amplitudes, further strengthening our argument for the association of LVA with alcoholism vulnerability. As expected, P300 amplitude was reduced in alcoholics, however, it was lowest in alcoholics with comorbid anxiety disorders and highest in individuals with anxiety disorders alone. In order to obtain sufficient power to map genes for alcoholism we have also studied a Plains American Indian tribe that has a high prevalence of alcoholism. We now have a complete dataset on 365 tribal members including EEGs and ERPs, blind-rated DSM-III-R psychiatric diagnoses and DNA. Preliminary studies confirm the relationship of LVA with alcoholism and anxiety disorders. We have started candidate gene analyses and have found that in both Bethesda and Plains Indian women, the low activity Met allele (and particularly the Met/Met homozygote) of the catechol-O-methyltransferase (COMT) functional polymorphism Val158Met is associated both with LVA and harm avoidance, a dimensional measure of anxiety. We have also found that LVA is associated with the DRD2 functional promoter polymorphism, -141CIns/Del. Haplotype analyses are currently underway in other key candidate genes for alcoholism and anxiety, including the GABAA chromosome 4 complex and GABAA alpha6. The Plains Indian pedigree has now been completed and we have formed a collaboration with a group in Germany to perform a whole genome linkage scan. We will soon be in a position to commence analyses for mapping genes for alcoholism. We have just completed the collection of another large dataset including EEG and ERP phenotypes, blind-rated DSM-IV psychiatric diagnoses, personality tests, demographics and DNA on 200 members of a Southeastern American Indian tribe with a very low rate of alcoholism; the lifetime prevalence of alcohol dependence is 10% in men and 1% in women. This tribe also has a low prevalence of other psychiatric disorders. We will be comparing the low and high alcoholism prevalence tribes for gene x environment interactions.